OP0101 B CELL POLYGENIC RISK SCORES ASSOCIATED WITH ANTI-DSDNA ANTIBODIES AND NEPHRITIS IN SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: A. Hedenstedt, S. Reid, A. Sayadi, M. L. Eloranta, E. Skoglund, K. Bolin, M. Frodlund, K. Lerang, A. Jonsen, S. Rantapää Dahlqvist, A. Bengtsson, A. Rudin, Ø. Molberg, C. Sjowall, J. Sandling, D. Leonard
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Lupus nephritis (LN) is one of the main clinical challenges in systemic lupus erythematosus (SLE) and a cause of significant morbidity and mortality. Genetic contribution to SLE pathogenesis is important, and genetic profiling through polygenic risk scores has been shown useful to stratify SLE patients according to dominating molecular disease mechanism.<sup>[1]</sup> This has not, however, been investigated for specific disease manifestations. <h3>Objectives</h3> In this work, we aimed to investigate associations between B cell polygenic risk scores (PRSs) and disease manifestations in SLE. <h3>Methods</h3> Female patients with SLE (n = 1248) and healthy control individuals (n = 519) were genotyped using Illumina's Global Screening Array. Two PRSs were calculated<sup>[2]</sup>, one including 20 GWS risk loci for SLE in genes assigned to B-cell related pathways according to the KEGG, GO and Reactome databases, and one including a subset of 12 of these genes limited to B-cell activation pathways. PRSs were defined as high in the highest quartile and low in quartile 1-3, and groups were compared by logistic regression (SPSS, version 28.0.1.0). HLA variants HLA-DRB1*03:01 and HLA-DRB1*15:01 were assessed in patients using tag SNPs. A p-value &lt; 0.05 was considered significant. <h3>Results</h3> SLE was more prevalent in individuals with high compared with a low SLE B cell PRS (OR 1.84 (1.42-2.38), p=4.0×10<sup>-6</sup>) and mean PRS was higher in cases than controls, 2.92 (2.88-2.96) for cases and 2.68 (2.63-2.74) for controls, p = 4.1 × 10<sup>-11</sup>). Immunologic disorder (ACR -82) and dsDNA antibodies were more prevalent among patients with a high compared with a low SLE B cell PRS (OR 1.44 (1.08-1.93), p=1.4×10<sup>-2</sup>, and OR 1.47 (1.07-2.01), p=1.8×10<sup>-2</sup>, for immunologic disorder and dsDNA antibodies, respectively). Also, effect sizes were augmented in patients with HLA risk serotypes HLA-DRB1*03:01 and HLA-DRB1*15:01, with the highest prevalence of dsDNA antibodies (87 %) demonstrated in patients with HLA-DRB1*03/15 +/+ combined with a high SLE B cell PRS (OR 1.64 (1.06-2.54), p = 0.028, for high vs low PRS), Figure 1. Anti-dsDNA antibodies were associated with a higher prevalence of class III or IV nephritis (OR 4.66 (2.78-7.80), p=5.2×10<sup>-9)</sup> and the prevalence of nephritis according to the ACR-82 criteria was higher in patients with a high compared to patients with a low B cell activation PRS (OR 1.32 (1.00-1.74), p = 0.048). Numerically, a higher prevalence of nephritis (ACR -82) was observed for patients with a high compared with a low SLE B cell PRS, but the difference was not statistically significant (OR 1.20 (0.91-1.59), p = 0.19). <h3>Conclusion</h3> High genetic burden related to B cell function is associated with dsDNA antibody development and LN. Assessing B cell PRSs may be important in order to determine immunologic pathways influencing SLE and to predict clinical phenotype. <h3>References</h3> [1]Sandling, J.K. <i>et al.</i> Molecular pathways in patients with systemic lupus erythematosus revealed by gene-centred DNA sequencing. <i>Ann Rheum Dis</i><b>80</b>, 109-117 (2021). [2]Reid, S. <i>et al.</i> High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus. <i>Ann Rheum Dis</i><b>79</b>, 363-369 (2020). <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.